Beneficial Effect of Human Induced Pluripotent Stem Cell-Derived Neural Precursors in Spinal Cord Injury Repair

Abstract

Despite advances in our understanding and research of induced pluripotent stem cells (iPSCs), their use in clinical practice is still limited due to lack of preclinical experiments. Neural precursors (NPs) derived from a clone of human iPSCs (IMR90) were used to treat a rat spinal cord lesion 1 week after induction. Functional recovery was evaluated using the BBB, beam walking, rotarod, and plantar tests. Lesion morphology, endogenous axonal sprouting, graft survival, and iPSC-NP differentiation were analyzed immunohistochemically. Quantitative polymerase chain reaction (qPCR) was used to evaluate the effect of transplanted iPSC-NPs on endogenous regenerative processes and also to monitor their behavior after transplantation. Human iPSC-NPs robustly survived in the lesion, migrated, and partially filled the lesion cavity during the entire period of observation. Transplanted animals displayed significant motor improvement already from the second week after the transplantation of iPSC-NPs. qPCR revealed the increased expression of human neurotrophins 8 weeks after transplantation. Simultaneously, the white and gray matter were spared in the host tissue. The grafted cells were immunohistochemically positive for doublecortin, MAP2, bIII-tubulin, GFAP, and CNPase 8 weeks after transplantation. Human iPSC-NPs further matured, and 17 weeks after transplantation differentiated toward interneurons, dopaminergic neurons, serotoninergic neurons, and ChAT-positive motoneurons. Human iPSCNPs possess neurotrophic properties that are associated with significant early functional improvement and the sparing of spinal cord tissue. Their ability to differentiate into tissue-specific neurons leads to the long-term restoration of the lesioned tissue, making the cells a promising candidate for future cell-based therapy of SCI.

The effect of magnetic nanoparticles on neuronal differentiation of induced pluripotent stem cell-derived neural precursors

“…The expression profile corresponds to previous flow cytometry analysis of the same iPSC-NPs during pre-differentiation in vitro. 20,43 The presence of A2B5 and CD44 in differentiating cells confirms the heterogeneity of the differentiating population and is also in agreement with Romanyuk et al 43 Increased expression of the neuronal marker β-III-tubulin during differentiation corresponds to our immunocytochemical data. The majority of differentiating cells were positive for β-III-tubulin and NF160.…”

Induced Pluripotent Stem Cell Transplantation Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…To arrive at robust conclusions, data were discussed when an outcome was reported from at least three simultaneous comparisons. In our present meta-analysis, we included six publications with eight comparisons [26][27][28][29][30][31]. The most obvious finding to emerge from our analyses was that in rats with SCI, iPSC transplantation significantly promotes the locomotor recovery according to the BBB score.…”

“…In our metaanalysis, only one publication [27] mentioned the use of triple drug immunosuppression containing Cyclosporine A (10 mg/kg), azathioprine sodium (2 mg/kg), methylprednisolone (2 mg/kg, tapered to 0.5 mg/kg) and methylprednisolone (2 mg/kg, tapered to 0.5 mg/kg) to prevent graft rejection. Generally, it is necessary to use initial combined immunosuppressive therapy in order to achieve consistent cell survival at intervals of 2-2.5 months after grafting [46].…”

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

“…A number of these studies reported significant therapeutic benefit when NSCs/NPCs derived from either mouse (Tsuji et al, 2010) or human (Fujimoto et al, 2012; Nori et al, 2011; Romanyuk et al, 2014) iPS cells were transplanted into contusion or cavity-type models of rodent SCI, as well as in non-human primate models (Kobayashi et al, 2012). Unlike our current work, these studies did not focus on, or achieve, targeted replacement of astrocytes in the injured spinal cord.…”